The present invention relates to intermediates for the synthesis of vitamin D derivatives useful as drugs and processes for the preparation of the same. More particularly it relates to intermediates for the synthesis of 1xcex1-hydroxyvitamin D derivatives useful as drugs such as osteogenesis promoters, tumorous cell growth inhibitors, immunosuppressants, anti-hypercalcemia drugs, therapeutic agents for inflammatory respiratory diseases and the like and processes for the preparation of the same.
It has hitherto been disclosed that vitamin D compounds and metabolites thereof play a highly important role as control substances of metabolism of in vivo calcium or phosphates in patent publications and general literature. Processes according to JP-B (hereinafter JP-B refers to Japanese Examined Patent Publication) No. 2-24268 and Tetrahedron Letters, 1992, 33, 105 are known as processes for the preparation of the vitamin D compounds.
Robert Henry Hesse et al. disclose processes for the preparation of vitamin D derivatives represented by the formula (5) from vitamin D2 in nine steps: 
(JP-B No. 2-24268); however, it may be scarcely said that the processes are industrial processes for the preparation because toxic selenium dioxide (SeO2) is used in steps of introducing a hydroxy group in the course of the processes. 
On the other hand, Mercedes Torneiro, L. Castedo, W. H. Okamura et al. disclose processes for the preparation of vitamin D derivatives represented by the formula: 
by a coupling reaction of compounds represented by the general formula (4): 
with compounds represented by the following general formula (6). 
For example, Tetrahedron Letters, 1992, 33, 105 describes an example of protecting a tertiary hydroxy group at the side chain terminal of a substituent Y with methoxymethyl group (MOM: xe2x80x94CH2OCH3) and reacting the protected compound. 
Further, Tetrahedron Letters, 1998, 29, 1203 and Tetrahedron 1991, 47, 3485 describe an example of ketalizing and protecting the carbonyl group in the side chain of the substituent Y and reacting the protected compound. 
In addition, Journal of American Chemical Society (J. Am. Chem. Soc.), 1991, 113, 6958 describes an example of reaction with a compound having a tertiary hydroxy group at the side chain terminal of the substituent Y. 
However, nothing is known about an example of coupling reaction with a compound having a primary hydroxy group at the side chain terminal of the substituent Y or a compound having the primary hydroxy group protected with a protecting group. 
By the way, coupling reaction of an acetylene compound with a triflate derivative (R-OTf) is known as the Stille reaction [for example, Stille et al., Journal of Organic Chemistry (J. Org. Chem.), 1985, 50, 2302]. The reaction is carried out by heating the acetylene compound and the triflate derivative in the presence of a palladium catalyst [Pd(0) or Pd(II)] and an additive [for example, triethylamine or lithium chloride (LiCl)] in a solvent (for example, tetrahydrofuran, ethanol, dimethylformamide or dimethyl sulfoxide) to prepare the objective coupling product.
An example of preparing vitamin D3 derivatives utilizing the reaction conditions has been reported by Okamura et al. [for example, Journal of American Chemical Society (J. Am. Chem. Soc.), 1991, 113, 6958].
Accordingly, an object of the present invention is to provide novel intermediates for the synthesis of 1xcex1-hydroxyvitamin D derivatives.
Another object of the present invention is to provide novel processes for the preparation of intermediates for the synthesis of the 1xcex1-hydroxyvitamin D derivatives.
As a result of intensive studies made on the objects, the inventors have achieved the following invention. Namely, the present invention is a process for the preparation of a compound represented by the formula (2): 
wherein, R1 and R2 are each the same as in the formula (4), which comprises reacting a compound represented by the formula (1): 
wherein, Tf represents SO2CF3, with a compound represented by the formula (4): 
wherein, R1 and R2 are each the same or different and represent each a hydrogen atom, a tri(C1-C7 hydrocarbon)silyl group, a diphenyl(C1-C7 hydrocarbon)silyl group or a group forming an acetal bond or an ester bond with an oxygen atom to which each of R1 and R2 is bound, in the presence of a palladium catalyst and an additive.
In addition, the present invention is a process for the preparation of a compound represented by the formula (3): 
wherein, R1 and R2 are each the same as in the above formula (4), which comprises, if necessary, adding a basic compound in order to lower the activity of a Lindlar catalyst in the presence of the Lindlar catalyst and hydrogen gas, then catalytically reducing the compound represented by the formula (2): 
wherein, R1 and R2 are each the same as in the above formula (4), and further heating the obtained product.
Furthermore, the present invention is a process for the preparation of a compound represented by the formula (5): 
wherein, R1 and R2 are each the same as in the above formula (4), which comprises oxidizing the compound represented by the formula (3): 
wherein, R1 and R2 are each the same as in the formula (4), with an oxidizing agent.
In addition, the present invention is the compound represented by the formula (1): 
wherein, Tf represents SO2CF3, the compound represented by the formula (2): 
wherein, R1 and R2 are each the same as in the above formula (4) and the compound represented by the formula (3): 
wherein, R1 and R2 are each the same as in the above formula (4), which are the intermediates for the synthesis of the vitamin D derivatives used in the processes for the preparation mentioned above.
The compound which is represented by the formula (1) and used as a raw material in the processes of the present invention is prepared from vitamin D2 through the following synthetic route: 
The preparation of the diol derivative from the vitamin D2 is realized by ozone oxidation reaction of the vitamin D2 by referring to known processes (J. Org. Chem., 1986, 51,1264 and the like).
The next preparation of a protected substance of the primary hydroxy group can be realized by introducing, for example t-butyldimethylsilyl group into the primary hydroxy group. In the process, the introduction of the protecting group can be realized by stirring t-butyldimethylsilyl chloride and the diol derivative in the presence of a basic compound such as imidazole in a solvent such as DMF, THF or methylene chloride at about normal temperature. The t-butyldimethylsilyl chloride or the like is used in an amount within the range of 1 to 1.5 equivalents based on 1 equivalent of the primary hydroxyl group.
The next preparation of the ketone derivative can be carried out by oxidation reaction of the secondary hydroxy group which is the protected derivative of the primary hydroxy group under various oxidizing conditions by using an oxidizing agent, for example MnO2 in acetone solvent or an Ru catalyst and NMO (N-methylmorpholine N-oxide), oxalyl chloride, DMSO and triethylamine in acetone solvent.
The next preparation of the triflate derivative can be realized by reacting, for example the ketone derivative with N-phenyltrifluoromethanesulfonimide (PhN(CF3SO2)2) and LDA (lithium diisopropylamide) in THF solvent. The preparation of the triflate derivative can be carried out by referring to the conditions for preparing the triflate derivative described in, for example Journal of American Chemical Society (J. Am. Chem. Soc.), 1991, 113, 6958.
The protecting group of the primary hydroxy group can subsequently be eliminated to prepare the compound represented by the formula (1). The elimination of the protecting group, i.e. silyl group can be realized by reaction in a solution of Bu4NF in THF or a solution of HF-pyridine in acetonitrile. An amount of the Bu4NF or HF-pyridine required for the elimination of the protecting group is sufficiently used, and the reaction is usually conducted at a reaction temperature within the range of 0xc2x0 C. to 80xc2x0 C.
The compound represented by the above formula (4) is a known compound and can be prepared from (S)-(+)-carvone through the following synthetic route according to the process described in, for example Journal of Organic Chemistry (J. Org. Chem.), 1989, 54, 4027. 
The amounts of the compound represented by the above formula (1) and the compound represented by the above formula (4) to be used for the coupling reaction for the preparation of the compound represented by formula (2) are stoichiometrically equimolar; however, either one, usually a more readily available one is used in a small excess for surely completing the reaction.
A catalyst such as Pd(II) or Pd(0) can be employed as the palladium catalyst used for the coupling reaction. Pd(OAc)2, PdCl2(PhCN)2, Pd(Ph3P)2Cl2, Pd2(dba)3, Pd(Ph3P)4, Pd(dppe)2 and the like are cited as typical examples of the catalyst.
The amount of the palladium catalyst to be used herein is within the range of is 0.5 to 100 mol %, preferably 1.0 to 30 mol % based on 1.0 mol of the compound represented by the above formula (1). In the process, the reaction may be carried out by adding a phosphorus compound such as triphenylphosphine or 1,2-bis(diphenylphosphino)ethane (dppe) for the purpose of preparing a more active Pd(0)-tertiary phosphine complex in the reaction system.
Examples of the additive to be used for the coupling reaction include triethylamine, diisopropylethylamine, pyridine, quinoline, lithium chloride and the like. The amount of the additive to be used is 1 to 20 equivalents, preferably 1 to 5 equivalents based on 1 equivalent of the palladium catalyst.
Examples of the reaction solvent include tetrahydrofuran, ethanol, dimethylformamide, dimethyl sulfoxide and the like. The amount of the solvent to be used is within the range of 1 to 500 mL, preferably 10 to 200 mL based on 1 g of the compound represented by the above formula (1). The reaction temperature used is usually within the range of room temperature to the boiling point of the solvent. The reaction time varies with the reaction solvent and reaction temperature to be used and is usually determined while monitoring the disappearance of the substrate and the formation of the objective substance by thin-layer chromatography, HPLC or the like. The reaction time, however, is usually about 1 to 30 hours.
The compound which is represented by the above formula (2) and prepared by the processes of the present invention can be derivatized into the compound represented by the above formula (3) by, if necessary, carrying out catalytic reduction or thermal isomerization.
The derivation of the compound represented by the above formula (2) into the compound represented by the above formula (3) is carried out by initially catalytically reducing the compound represented by the above formula (2). For example, reference can be made to known literature such as Shin Jikken Kagaku Koza (Vol. 15, Oxidation and Reduction, p. 425); J. Chem. Soc. (C), 1971, 2963; Tetrahedron, 47, 3485 or the like.
Specifically, the catalytic reduction is carried out by dissolving the compound represented by the above formula (2) in a solvent inert to the catalytic reduction, for example, a hydrocarbon solvent such as pentane, hexane or isooctane; an ether solvent such as diethyl ether or THF; or an alcoholic solvent such as MeOH or EtOH, adding a catalyst (a Lindlar catalyst is frequently used for selective reduction of a carbon-carbon triple bond into a carbon-carbon double bond) and, if necessary, a basic compound such as quinoline for the purpose of lowering the activity of the catalyst with hydrogen under atmospheric pressure or under pressure (use under an excessively high pressure is undesirable).
The amount of the catalyst to be used herein is 0.1 to 50 g, usually about 1.0 to 20 g based on 100 g of the substrate. The amount of the basic compound to be added is within the range of 0 to 50 g based on 1.0 g of the amount of the catalyst to be used. The reaction temperature to be used is usually within the range of room temperature to 40xc2x0 C. Since the reaction time varies with the reaction solvent, reaction temperature and hydrogen pressure to be used, the reaction temperature is preferably determined while monitoring the stop of consumption of the hydrogen, disappearance of the substrate and the formation of the objective substance by HPLC.
Since the reduced product is frequently present as a mixture represented by the formula, the mixture is preferably thermally isomerized by heating to produce the objective compound represented by the above formula (3). 
When the reaction temperature of the thermal isomerization herein is too low, there are problems that the thermal isomerization proceeds very slowly or does not proceed. On the other hand, when the reaction temperature is too high, there is a fear of causing the thermal decomposition of the isomerized compound. Thereby, the reaction temperature is within the range of 50 to 200xc2x0 C., preferably 80 to 150xc2x0 C. Although the mixture itself can directly be heated for the thermal isomerization, a solvent having the boiling point within the range of 80 to 150xc2x0 C. is usually used. A hydrocarbon solvent such as isooctane is particularly preferable as the solvent; however, a solvent inert to the mixture can be used as the solvent for the thermal isomerization. The amount of the solvent to be used is within the range of 0 to 1000 mL, preferably 0 to 200 mL based on 1 g of the mixture. After completing the reduction reaction, the mixture can directly be heated; however, the mixture may be heated after separating the catalyst by filtration or the like. Otherwise, the solvent is distilled off, and the thermal isomerization may be carried out after distilling off the solvent and replacing the solvent with a different solvent. After purification by silica gel chromatography or the like, the purified product may be thermally isomerized.
The compound which is represented by the above formula (3) and prepared by the processes of the present invention can be derived into the compound represented by the above formula (5) by, if necessary, oxidizing the compound represented by the above formula (3).
The derivation of the compound represented by the above formula (3) into the compound represented by the above formula (5) can be carried out by using oxalyl chloride, DMSO or triethylamine as an oxidizing agent and using dichloromethane, toluene, acetone, acetonitrile or hexane as a reaction solvent by referring to known literature, for example, Shin Jikken Kagaku Koza (Vol. 15, Oxidation and Reduction, p. 802); J. Org. Chem., 1979, 44, 4148; J. Org. Chem., 1978, 43, 2480; and Synthesis, 1978, 297. Furthermore, the derivation can be realized by oxidation reaction under the so-called Swern oxidation reaction conditions or oxidation with KMnO4, MnO2, the Jones reagent, the Collins reagent, an oxidizing agent of an Ru catalyst and NMO (N-methylmorpholine N-oxide) in acetone solvent.
An example of preparing a 1xcex1-hydroxyvitamin D derivative will be described hereinafter. 
A pharmaceutical composition comprising the 1xcex1-hydroxyvitamin D derivative which is the final product is used as a therapeutic agent for inflammatory pulmonary diseases. Examples of the inflammatory pulmonary diseases include one or two or more kinds of inflammatory respiratory diseases selected from the group consisting of acute upper airway infections, chronic sinusitis, allergic rhinitis, chronic lower airway infections, emphysema, pneumonia, asthma, sequelae of pulmonary tuberculosis, acute respiratory distress syndrome, cystic fibrosis and pulmonary fibrosis.